We recently discovered that a single nucleotide polymorphism in the human lymphoid tyrosine phosphatase LYP (encoded by the PTPN22 gene) is associated with type 1 diabetes, an autoimmune disease that arises from T lymphocyte-mediated destruction of insulin-producing B-cells in the pancreas (Nature Genetics 36, 337-338). LYP is expressed only in white blood cells and acts as a gatekeeper of T lymphocyte activation. The molecular mechanism by which LYP tempers T lymphocyte activation involves the formation of a complex between LYP and the negative regulatory kinase Csk. We have found that the autoimmune- disposing LYP variant, LYP-W620, cannot bind to Csk and our new preliminary data show that LYP-W620 regulates TCR signaling in a different way than the more common LYP-R620. We hypothesize that LYP genetic polymorphism alters the threshold of T cell activation, thereby predisposing carriers to a misdirected immune response against autoantigens in pancreatic islets or other tissues. In this proposal we wish to generate mouse models carrying T cell-specific expression of the 2 genetic variants of the phosphatase and perform their phenotypic analysis. This will allow us to gain important insights about the effect of the polymorphism on TCR signaling, T cell development and differentiation, and the mechanism of association between the R620W polymorphism and type 1 diabetes. The new mouse models will then be available for further immunological analyses and for studies aimed at validating new pharmacologic approaches to disease prevention or intervention in carriers of the LYP-W620 variant. [unreadable] [unreadable] [unreadable]